The beneficial effects of ciprofloxacin on survival and hepatic regenerative activity in a rat model of fulminant hepatic failure.
Recently, we reported that ciprofloxacin, an antimicrobial agent with gamma-aminobutyric acid (GABA(A)) receptor antagonist properties, significantly increases hepatic regenerative activity in animal models of alcohol-induced liver disease and cirrhosis. In the present study, we documented the effects of ciprofloxacin on survival and hepatic regeneration in a D-galactosamine (D-gal)-induced model of acute hepatic injury in rats. One hundred nineteen adult, male Sprague-Dawley rats (n = 19-20/group) were treated with intraperitoneal D-gal (total dose: 2.5 g/kg), followed by gastric gavage with either saline, ciprofloxacin (10, 50, or 100 mg/kg), norfloxacin (250 mg/kg), or intraperitoneal putrescine (300 micromol/kg), a potent hepatic growth promoter. Mortality rates were then documented over a 4-day period. An additional 45 rats (n = 15/group) received a sublethal dose of D-gal (1.0 g/kg), followed by gastric gavage with either saline or ciprofloxacin (100 mg/kg), or intraperitoneal putrescine (300 micromol/kg). In these rats, hepatic regenerative activity was documented at 12, 24, and 60 hours post-D-gal by 3H-thymidine incorporation into hepatic DNA and proliferating cell nuclear antigen (PCNA) staining. In the survival study, a dose-response effect of ciprofloxacin on survival was observed (ciprofloxacin: 10 mg/kg, 10%; 50 mg/kg, 26%; and 100 mg/kg, 35%) with the results in the 100-mg/kg-treated group being significant when compared with the 5% survival rate in saline-treated controls (P < .05). Survival figures in the norfloxacin- and putrescine-treated groups were not significantly improved (15% and 25%, respectively). In the regeneration study, compared with the D-gal + saline-treated control group, DNA synthesis rates at 60 hours were increased in the D-gal + ciprofloxacin and D-gal + putrescine groups (10.2 +/- 3.3 vs. 18.2 +/- 5.1 and 18.8 +/- 6.8 x 10(3) dpm/mg DNA respectively; P < .05). The results of PCNA staining also supported enhanced hepatic regeneration in the ciprofloxacin-treated group at 60 hours (saline, 13.4 +/- 3.7; ciprofloxacin, 47.4 +/- 7.3; and putrescine, 8.4% +/- 2.8% hepatocytes staining positive). Ciprofloxacin at a dose of 100 mg/kg significantly improves survival and hepatic regenerative activity in this animal model of acute hepatic injury.
Kaita
K D
KD
Department of Medicine, University of Manitoba, Winnipeg, Canada.
Assy
N
N
Gauthier
T
T
Zhang
M
M
Meyers
A F
AF
Minuk
G Y
GY
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D017093:Liver Failure / Q000401:mortality / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009643:Norfloxacin / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011700:Putrescine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013997:Time Factors
D000890:Anti-Infective Agents; D018809:Proliferating Cell Nuclear Antigen; D002939:Ciprofloxacin; D004247:DNA; D000410:Alanine Transaminase; D009643:Norfloxacin; D011700:Putrescine